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Colorectal cancer remains a significant cause of mortality worldwide. A spiro-acridine derivative, ( E )-1'-((4-bromobenzylidene)amino)-5'-oxo-1',5'-dihydro-10 H -spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-19), showed significant cytotoxicity in HCT-116 colorectal carcinoma cells (half maximal inhibitory concentration, IC50 = 10.35 ± 1.66 µM) and antioxidant effects after 48 h of treatment. In this study, Molegro Virtual Docker v.6.0.1 software was used to investigate the interactions between AMTAC-19 and the Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), and p38 Mitogen-Activated Protein Kinase α (p38α MAPK). In vitro assays were conducted in HCT-116 cells to evaluate the effect of AMTAC-19 on the modulation of these proteins' activities using flow cytometry. Furthermore, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in the presence or absence of ERK1/2, JNK, and p38 MAPK inhibitors was used to evaluate the involvement of these enzymes in AMTAC-19 cytotoxicity. ROS production was assessed using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay at various incubation times (30 min, 1 h, 6 h, 12 h, and 24 h), and the MTT assay using N-acetyl-L-cysteine (NAC) was performed. In silico results indicated that AMTAC-19 interacts with ERK1, JNK1, and p38α MAPK. Additionally, AMTAC-19 activated ERK1/2 and JNK1 in HCT-116 cells, and its cytotoxicity was significantly reduced in the presence of ERK1/2 and JNK inhibitors. AMTAC-19 also induced a significant increase in ROS production (30 min and 1 h), while NAC pretreatment reduced its cytotoxicity. These findings support AMTAC-19's in vitro antitumor effect through ROS-dependent activation of ERK and JNK pathways., Competing Interests: The authors declare no conflicts of interest.

Chalcones are direct precursors in the biosynthesis of flavonoids. They have an α,β-unsaturated carbonyl system which gives them broad biological properties. Among the biological properties exerted by chalcones, their ability to suppress tumors stands out, in addition to their low toxicity. In this perspective, the present work explores the role of natural and synthetic chalcones and their anticancer activity in vitro reported in the last four years from 2019 to 2023. Moreover, we carried out a partial least square (PLS) analysis of the biologic data reported for colon adenocarcinoma lineage HCT-116. Information was obtained from the Web of Science database. Our in silico analysis identified that the presence of polar radicals such as hydroxyl and methoxyl contributed to the anticancer activity of chalcones derivatives. We hope that the data presented in this work will help researchers to develop effective drugs to inhibit colon adenocarcinoma in future works.

Sesquiterpene lactone (SL) subtypes including hirsutinolide and cadinanolide have a controversial genesis. Metabolites of these classes are either described as natural products or as artifacts produced via the influence of solvents, chromatographic mobile phases, and adsorbents used in phytochemical studies. Based on this divergence, and to better understand the sensibility of these metabolites, different pH conditions were used to prepare semisynthetic SLs and evaluate the anti-inflammatory and antiproliferative activities. Therefore, glaucolide B ( 1 ) was treated with various Brønsted-Lowry and Lewis acids and bases-the same approach was applied to some of its derivatives-allowing us to obtain 14 semisynthetic SL derivatives, 10 of which are hereby reported for the first time. Hirsutinolide derivatives 7a (CC 50 = 5.0 µM; SI = 2.5) and 7b (CC 50 = 11.2 µM; SI = 2.5) and the germacranolide derivative 8a (CC 50 = 3.1 µM; SI = 3.0) revealed significant cytotoxic activity and selectivity against human melanoma SK-MEL-28 cells when compared with that against non-tumoral HUVEC cells. Additionally, compounds 7a and 7c.1 showed strongly reduced interleukin-6 (IL-6) and nitrite (NOx) release in pre-treated M1 macrophages J774A.1 when stimulated with lipopolysaccharide. Despite the fact that hirsutinolide and cadinanolide SLs may be produced via plant metabolism, this study shows that acidic and alkaline extraction and solid-phase purification processes can promote their formation., Competing Interests: The authors declare no conflicts of interest.

Introduction: Despite numerous scientific advances, cancer continues to be one of the main causes of death in the world. This situation has driven the search for promising molecules. Lichen substances have been widely described for their pharmacological potential., Objective: The present study evaluated the antitumour potential of a depsidone isolated from Parmotrema concurrens - salazinic acid (SAL) - through in vitro , in vivo and in silico studies., Methods: The molecule was isolated from the acetonic extract of the lichen and recrystallized in acetone. The macrophage J774, sarcoma-180 and MDA-MB-231 cell lines were used for the MTT cytotoxicity assay. The antitumor assay used a murine model (Swiss albino mice) with sarcoma-180. The animals were treated for seven consecutive days with doses of SAL (25 and 50 mg/kg) and 5-fluorouracil (20 mg/kg)., Results: Its purity was determined using high-performance liquid chromatography (94%), and its structure was confirmed by H 1 and C 13 nuclear magnetic resonance. SAL was not considered toxic to cancer cell lines, showing cell viability rates of 79.49 ± 4.15% and 86.88 ± 1.02% for sarcoma-180 and MDA-MB-231, respectively. The tumour inhibition rate was greater than 80% in the animals treated with SAL and 65% for those that received 5-fluorouracil. Simulations of molecular dynamics to estimate the flexibility of the interactions between human thymidylate synthase and derivatives of SAL and 5-fluorouracil revealed that SAL exhibited greater enzymatic interaction capacity, with highly favourable energy, compared to 5-fluorouracil., Conclusion: The present results demonstrate the potential of salazinic acid as a tumour inhibition agent., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Gastrointestinal stromal tumors (GISTs) are unusual cancers, which are developed in specialized cells in the gastrointestinal tract wall. Various strategies involving single-agents, combinations, and rapid complementary inhibitor cycling are now being used to control such tumors. Based on promising early clinical trial experience, certain novel KIT and PDGFRA tyrosine kinase inhibitors have shown advanced clinical development. Resistance to tyrosine kinase inhibitors has brought immense difficulties, with patients now requiring additional therapeutic options. This review describes and discusses the last five years (2016-2020) in developing novel c-KIT kinase inhibitors using virtual screening and docking approaches. Computational techniques can be used to complement experimental studies to identify new candidate molecules for therapeutic use. Molecular modeling strategies allow the analysis of the required characteristics that compounds must have to effectively bind c-KIT. Through such analyses, it is possible to both discover and design novel inhibitors against cancer-related proteins that play a critical role in tumor development (including mutant strains). Docking showed potential in the detection of the key residues responsible for ligand recognition and is very helpful to understand the interactions in the active site that can be used to develop new compounds/classes of anticancer drugs and help millions of cancer patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: Selenium-based compounds have antitumor potential. We used a ligand-based virtual screening analysis to identify selenoglycolicamides with potential antitumor activity. Results & Conclusion: Compounds 3 , 6 , 7 and 8 were selected for in vitro cytotoxicity tests against various cell lines, according to spectrophotometry results. Compound 3 presented the best cytotoxicity results against a promyelocytic leukemia line (HL-60) and was able to induce cell death at a frequency similar to that observed for doxorubicin. The docking study showed that compound 3 has good interaction energies with the targets caspase-3, 7 and 8, which are components of the apoptotic pathway. These results suggested that selenium has significant pharmacological potential for the selective targeting of tumor cells, inducing molecular and cellular events that culminate in tumor cell death.

Liver cancers are one of the leading fatal diseases among malignant neoplasms. Current chemotherapeutic treatments used to fight these illnesses have become less efficient in terms of both efficacy and safety. Therefore, there is a great need of search for new anti-liver cancer agents and this can be accelerated by using computer-aided drug discovery approaches. In this work, we report the development of the first cell-based multi-target model based on quantitative structure-activity relationships (CBMT-QSAR) for the design and prediction of chemicals as anticancer agents against 17 liver cancer cell lines. While having a good quality and predictive power (accuracy higher than 80%) in the training and test sets, respectively, the CBMT-QSAR model was employed as a tool to directly extract suitable fragments from the physicochemical and structural interpretations of the molecular descriptors. Some of these desirable fragments were assembled, leading to the virtual design of eight molecules with drug-like properties, with six of them being predicted as versatile anticancer agents against the 17 liver cancer cell lines reported here.

Background: Nanotechnology has contributed a great deal to the field of medical science. Smart drugdelivery vectors, combined with stimuli-based characteristics, are becoming increasingly important. The use of external and internal stimulating factors can have enormous benefits and increase the targeting efficiency of nanotechnology platforms. The pH values of tumor vascular tissues are acidic in nature, allowing the improved targeting of anticancer drug payloads using drug-delivery vectors. Nanopolymers are smart drug-delivery vectors that have recently been developed and recommended for use by scientists because of their potential targeting capabilities, non-toxicity and biocompatibility, and make them ideal nanocarriers for personalized drug delivery., Method: The present review article provides an overview of current advances in the use of nanoparticles (NPs) as anticancer drug-delivery vectors., Results: This article reviews the molecular basis for the use of NPs in medicine, including personalized medicine, personalized therapy, emerging vistas in anticancer therapy, nanopolymer targeting, passive and active targeting transports, pH-responsive drug carriers, biological barriers, computer-aided drug design, future challenges and perspectives, biodegradability and safety., Conclusion: This article will benefit academia, researchers, clinicians, and government authorities by providing a basis for further research advancements., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Computer-Aided Drug Design (CADD) techniques have garnered a great deal of attention in academia and industry because of their great versatility, low costs, possibilities of cost reduction in in vitro screening and in the development of synthetic steps; these techniques are compared with highthroughput screening, in particular for candidate drugs. The secondary metabolism of plants and other organisms provide substantial amounts of new chemical structures, many of which have numerous biological and pharmacological properties for virtually every existing disease, including cancer. In oncology, compounds such as vimblastine, vincristine, taxol, podophyllotoxin, captothecin and cytarabine are examples of how important natural products enhance the cancer-fighting therapeutic arsenal. In this context, this review presents an update of Ligand-Based Drug Design and Structure-Based Drug Design techniques applied to flavonoids, alkaloids and coumarins in the search of new compounds or fragments that can be used in oncology. A systematical search using various databases was performed. The search was limited to articles published in the last 10 years. The great diversity of chemical structures (coumarin, flavonoids and alkaloids) with cancer properties, associated with infinite synthetic possibilities for obtaining analogous compounds, creates a huge chemical environment with potential to be explored, and creates a major difficulty, for screening studies to select compounds with more promising activity for a selected target. CADD techniques appear to be the least expensive and most efficient alternatives to perform virtual screening studies, aiming to selected compounds with better activity profiles and better "drugability"., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The application of in silico tools in the development of anti cancer drugs., Objective: The summing of different computer aided drug design approaches that have been applied in the development of anti cancer drugs., Methods: Structure based, ligand based, hybrid protein-ligand pharmacophore methods, Homology modeling, molecular docking aids in different steps of drug discovery pipeline with considerable saving in time and expenditure. In silico tools also find applications in the domain of cancer drug development., Results: Structure-based pharmacophore modeling aided in the identification of PUMA inhibitors, structure based approach with high throughput screening for the development of Bcl-2 inhibitors, to derive the most relevant protein-protein interactions, anti mitotic agents; I-Kappa-B Kinase β (IKK- β) inhibitor, screening of new class of aromatase inhibitors that can be important targets in cancer therapy., Conclusion: Application of computational methods in the design of anti cancer drugs was found to be effective., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cancer is the main cause of death, so the search for active agents to be used in the therapy of this disease, is necessary. According to studies conducted, substances derived from natural products have shown to be promising in this endeavor. To these researches, one can associate with the aid of computational chemistry, which is increasingly gaining popularity, due to the possibility of developing alternative strategies that could help in choosing an appropriate set of compounds, avoiding unnecessary expenses with resources that would generate unwanted substance. Thus, the objective of this study was to carry out an approach to several studies that apply different methods of virtual screening to select natural products with potential anticancer activity. This review presents reports of studies conducted with some natural products, such as coumarin, quinone, tannins, alkaloids, flavonoids and terpenes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Tubulin polymerization inhibitors interfere with microtubule assembly and their functions lead to mitotic arrest, therefore they are attractive target for design and development of novel anticancer compounds., Objective: The proposed novel and effective structures following the use of three-dimensionalquantitative structure activity relationship (3D-QSAR) pharmacophore based virtual screening clearly demonstrate the high efficiency of this method in modern drug discovery., Methods: Combined computational approach was applied to extract the essential 2D and 3D features requirements for higher activity as well as identify new anti-tubulin agents., Results: The best quantitative pharmacophore model, Hypo1, exhibited good correlation of 0.943 (RMSD=1.019) and excellent predictive power in the training set compounds. Generated model AHHHR, was well mapped to colchicine site and three-dimensional spatial arrangement of their features were in good agreement with the vital interactions in the active site. Total prediction accuracy (0.92 for training set and 0.86 for test set), enrichment factor (4.2 for training set and 4.5 for test set) and the area under the ROC curve (0.86 for training set and 0.94 for the test set), the developed model using Extended Class FingerPrints of maximum diameter 4 (ECFP_4) was chosen as the best model., Conclusion: Developed computational platform provided a better understanding of requirement features for colchicine site inhibitors and we believe the results of this study might be useful for the rational design and optimization of new inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Since ancient times, natural products have been used in treating various diseases effectively and safely. Nowadays, these natural compounds are submitted to sophisticated methodologies from isolation, computing, analytical, and even serving as pharmacophore suggestions for synthesis. The substances extracted from marine species, plants, and microorganisms present activities beneficial to our health, including protection against malignant tumors. The topoisomerase enzymes play an important role in DNA metabolism, and searching for enzyme inhibitors is an important target in the search for new anticancer drugs. This review discusses this problem, reporting research involving alkaloids, terpenes, flavonoids, xanthones, coumarins, acetogenins, and in addition, includes a docking study with our Brazilian diterpenes to topoisomerases I and II. The better compound, the trachylobane 1, forms one hydrogen bond when submitted to docking with Topo I (with the ASP533 residue) and two with residues in Topo II (THR213 and TYR188). The difference observed in the energy of formation can be attributed to hydrogen-bond interactions. The difference observed in the energy of formation can be attributed to hydrogen-bond interactions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost. The approach has been successfully used by many research groups around the world and has had very promising results with diseases having multifactorial profiles, like Alzheimer´s, Parkinson´s disease, cancer, inflammation, and hypertension among others. The purpose of this paper is to conduct an updated review of molecular hybridization and multitarget profiling (a rational drug design approach), and its applications to the design and discovery of novel hybrid compounds with anti-inflammatory, antimicrobial, anticancer and antiprotozoal (leishmaniasis, malaria, and schistosomiasis) activities over the last six years., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A series of 2-[(arylidene)amino]-cycloalkyl[b]thiophene-3-carbonitriles (2a-x) was synthesized by incorporation of substituted aromatic aldehydes in Gewald adducts (1a-c). The title compounds were screened for their antifungal activity against Candida krusei and Criptococcus neoformans and for their antiproliferative activity against a panel of 3 human cancer cell lines (HT29, NCI H-292 and HEP). For antiproliferative activity, the partial least squares (PLS) methodology was applied. Some of the prepared compounds exhibited promising antifungal and proliferative properties. The most active compounds for antifungal activity were cyclohexyl[b]thiophene derivatives, and for antiproliferative activity cycloheptyl[b]thiophene derivatives, especially 2-[(1H-indol-2-yl-methylidene)amino]- 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (2r), which inhibited more than 97 % growth of the three cell lines. The PLS discriminant analysis (PLS-DA) applied generated good exploratory and predictive results and showed that the descriptors having shape characteristics were strongly correlated with the biological data.

Some sesquiterpene lactones (SLs) are the active compounds of a great number of traditionally medicinal plants from the Asteraceae family and possess considerable cytotoxic activity. Several studies in vitro have shown the inhibitory activity against cells derived from human carcinoma of the nasopharynx (KB). Chemical studies showed that the cytotoxic activity is due to the reaction of alpha,beta-unsaturated carbonyl structures of the SLs with thiols, such as cysteine. These studies support the view that SLs inhibit tumour growth by selective alkylation of growth-regulatory biological macromolecules, such as key enzymes, which control cell division, thereby inhibiting a variety of cellular functions, which directs the cells into apoptosis. In this study we investigated a set of 55 different sesquiterpene lactones, represented by 5 skeletons (22 germacranolides, 6 elemanolides, 2 eudesmanolides, 16 guaianolides and nor-derivatives and 9 pseudoguaianolides), in respect to their cytotoxic properties. The experimental results and 3D molecular descriptors were submitted to Kohonen self-organizing map (SOM) to classify (training set) and predict (test set) the cytotoxic activity. From the obtained results, it was concluded that only the geometrical descriptors showed satisfactory values. The Kohonen map obtained after training set using 25 geometrical descriptors shows a very significant match, mainly among the inactive compounds (approximately 84%). Analyzing both groups, the percentage seen is high (83%). The test set shows the highest match, where 89% of the substances had their cytotoxic activity correctly predicted. From these results, important properties for the inhibition potency are discussed for the whole dataset and for subsets of the different structural skeletons.